Neuroleptic 2-piperidinoalkyl-1,4-benzodioxans

ABSTRACT

2-Piperidinoalkyl-1,4-benzodioxans, e.g. those of the formula ##STR1## and acid addition salts thereof are neuroleptic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of application Ser. No. 680,318, filedApr. 26, 1976, which in turn is a continuation-in-part of applicationSer. No. 589,118, filed June 23, 1975 (now U.S. Pat. No. 4,039,676).

SUMMARY OF THE DISCLOSURE

The present invention concerns and has for its object the provision ofnew 2-piperidinoalkyl-(1-benzofurans or -1,4-dioxans), more particularlyof those corresponding to Formula I ##STR2## wherein Ph is unsubstituted1,2-phenylene or 1,2-phenylene substituted by one to three identical ordifferent members selected from lower alkyl, hydroxy, mercapto, loweralkoxy, lower alkylenedioxy, benzyloxy, lower alkylthio, halogeno,trifluoromethyl, nitro, or amino; X is oxygen or sulfur; m is theinteger 0 or 1; n is an integer from 1 to 4; each of p and q is aninteger from 1 to 3, but (p+q) = 4; each of R₁ and R₂ is hydrogen, loweralkyl or HPh; R₃ is hydrogen, hydroxy, lower alkoxy, lower alkenyloxy,lower alkynyloxy, lower or higher alkanoyloxy and R₄ is lower alkyl,HPh-lower alkyl, HPh, unsubstituted naphthyl or naphthyl substituted asPh, unsubstituted furyl, thienyl, pyridyl, benzofuryl, benzothienyl,quinolyl or isoquinolyl or said heterocyclics substituted as Ph; or ofS-oxides or therapeutically acceptable acid addition salts thereof; ofcorresponding pharmaceutical compositions and of methods for thepreparation and application of these products, which are usefulneuroleptic agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The 1,2-phenylene group Ph is preferably monosubstituted, and itssubstituents illustrated by the following groups: lower alkyl, e.g.methyl, ethyl, n- or i-propyl or -butyl; hydroxy; mercapto; loweralkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or -butoxy, loweralkylenedioxy, e.g. methylenedioxy, 1,1- or 1,2-ethylenedioxy;benzyloxy; lower alkylthio, e.g. methylthio or ethylthio; halogeno, e.g.fluoro, chloro or bromo; trifluoromethyl; nitro or amino.

Of said integers m is preferably 1, when 1,4-benzodioxans or1,4-benzoxathians are depicted by Formula I, or it is 0, when1-benzofurans are depicted. The alkylene moiety C_(n) H_(2n)advantageously represents methylene, 1,1- or 1,2-ethylene, 1,2- or1,3-propylene, 1,2-, 1,3- or 1,4-butylene; and each p and q ispreferably two.

Each of R₁ and R₂ is preferably hydrogen, but also lower alkyl,advantageously methyl, or another of those mentioned above. Preferablyone thereof, especially R₂, may also be phenyl or substituted phenyl, asillustrated by H-Ph above.

The substituent R₃ is preferably free, etherified or esterified hydroxy,such as lower alkoxy, e.g. that mentioned above; lower alkenyloxy oralkynyloxy, preferably lower 2- or 3-(alkenyloxy or alkynyloxy), such asallyloxy, 2- or 3-butenyloxy; propargyloxy, 2- or 3-butynyloxy; lower orhigher alkanoyloxy, e.g. acetoxy, propionyloxy or pivalyloxy;octanoyloxy, decanoyloxy, undecanoyloxy, lauroyloxy, myristoyloxy,palmitoyloxy or stearoyloxy; but may also represent hydrogen.

The lower alkyl group R₄ is preferably a secondary or tertiary alkylgroup with 3 to 7 carbon atoms, such as i-propyl, i- or t-butyl, -pentylor -hexyl. An aralkyl group R₄ is preferably represented by HPh-C_(n)H_(2n), e.g. benzyl, 1- or 2-phenethyl. Most preferred groups R₄ arephenyl groups represented by HPh and illustrated above; but also 1- or2-naphthyl optionally substituted as shown for HPh. Heterocyclic R₄-groups are preferably unsubstituted 2- or 3-furyl or -thienyl; 2-, 3-or 4-pyridyl; 2- or 3-(1-benzofuryl or 1-benzothienyl); 2-, 3- or4-quinolyl or 1-, 3- or 4-isoquinolyl; or said groups substituted by oneto three lower alkyl, preferably methyl groups.

Due to the at least one nitrogen atom present in the compounds ofFormula I, they can be in the form of therapeutically useful acidaddition salts, e.g. derived from the acids listed below. The S-oxidesof the invention are preferably those of Formula I wherein X is SO. Asused above and hereinafter in connection with organic radicals orcompounds respectively, the term "lower" defines such with up to 7,preferably up to 4, and advantageously 1 or 2 carbon atoms; and the term"higher" defines such with 8 to 20, preferably 10 to 16 carbon atoms.

The compounds of the invention exhibit valuable pharmacologicalproperties, predominantly neuroleptic activity with a wide separation ofbeneficial and extra-pyramidal side effects not yet observed in otherneuroleptics, such as haloperidol. This can be demonstrated in animaltests, using advantageously mammals, such as mice, rats, dogs andespecially monkeys, as test objects. Said compounds are applied eitherenterally or parenterally, e.g. orally, subcutaneously,intraperitoneally or intravenously, for example, within gelatincapsules, suspended in cornstarch, or in the form of aqueous solutionsor suspensions respectively. The oral dosage may range between about 0.1and 10 mg/kg/day, preferably between about 0.5 and 5 mg/kg/day andadvantageously between about 1 and 2.5 mg/kg/day. Said compounds,exemplified by the2-[2-(4-hydroxy-4-phenylpiperidino)ethyl]-1,4-benzodioxan, or itshydrochloride, produce at the above oral doses, especially between about0.5 and 5 mg/kg/day, a decrease of the lever-pressing avoidanceresponses of squirrel monkeys. The test procedure used in the following:Monkeys were trained to press a lever to avoid the onset of an electricfoot shock. Each lever press postpones the shock for twenty-seconds.Whenever the monkey fails to press the lever once within a twenty-secondperiod, brief (0.5 sec.) shocks are delivered at twenty-second intervalsuntil the animal again presses the lever. Under control conditions themonkeys press the lever at a moderately steady rate and seldom receivemore than five or six shocks during a four-hour experimental session.Said compounds evaluated for neuroleptic activity, block the learnedconditioned avoidance behavior, manifested by a decrease in avoidanceresponding with a marked increase in shocks taken by the animal.

Accordingly, the compounds of the invention are useful preferably asneuroleptics, for example in the treatment or management of aggression,agitation, anxiety and pain in animals, preferably mammals. They arealso valuable intermediates for other preparations, advantageouslypharmacologically useful products.

Particularly useful are compounds of Formula I, wherein Ph is1,2-phenylene unsubstituted, mono or disubstituted by lower alkyl,hydroxy, mercapto, lower alkoxy, lower alkylenedioxy, benzyloxy, loweralkylthio, halogeno, trifluoromethyl, nitro or amino, X is oxygen orsulfur, m is the integer 0 or 1, n is an integer from 1 to 4, each of pand q is an integer from 1 to 3, but (p+q) = 4, each of R₁ and R₂ ishydrogen or lower alkyl, R₃ is hydrogen, hydroxy, lower alkoxy, lower 2-or 3-(alkenyloxy or alkynyloxy), lower or higher alkanoyloxy and R₄ islower alkyl, HPh-C_(n) H_(2n), HPh, unsubstituted furyl, thienyl orpyridyl, or said heterocyclics mono- or disubstituted by lower alkyl, ortherapeutically acceptable acid addition salts thereof.

Preferred compounds of the invention are those of Formula I, wherein Phis 1,2-phenylene unsubstituted, mono- or disubstituted by alkyl, alkoxyor alkylthio with up to 4 carbon atoms each, halogeno ortrifluoromethyl; X is oxygen, m is the integer 0 or 1, n is an integerfrom 2 to 4, each of p and q is the integer 2, each of R₁ and R₂ ishydrogen or alkyl with up to 4 carbon atoms, R₃ is hydrogen, hydroxy,alkoxy, 2- or 3-(alkenyloxy or alkynyloxy) with up to 4 carbon atoms, oralkanoyloxy with up to 16 carbon atoms and R₄ is secondary or tertiaryalkyl with 3 to 7 carbon atoms, HPh-CH₂, HPh, 2- or 3- furyl or-thienyl, 2-, 3- or 4-pyridyl; or therapeutically acceptable acidaddition salts thereof.

Outstanding an account of their usefulness are compounds of Formula II##STR3## wherein R is hydrogen, alkyl, alkoxy or alkylthio with up to 4carbon atoms each, halogeno or trifluoromethyl, x is the integer 1 or 2,y is an integer from 2 to 4, R" is hydrogen, hydroxy, alkoxy, 2- or3-(alkenyloxy) or alkynyloxy) with up to 4 carbon atoms, or alkanoyloxywith up to 16 carbon atoms and R' is secondary or tertiary alkyl with 3to 7 carbon atoms, R_(x) -benzyl, R_(x) -phenyl, 2- or 3-furyl or-thienyl, 2-, 3- or 4-pyridyl; or therapeutically acceptable acidaddition salts thereof.

More preferred are compounds of Formula II, wherein R is hydrogen,methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, fluoro, chloro ortrifluoromethyl, x is the integer 1 or 2, y is the integer 2 or 3, R" ishydrogen, hydroxy, methoxy, ethoxy, allyloxy, propargyloxy, oralkanoyloxy with 2 to 12 carbon atoms and R' is i-propyl, i- or t-butyl,benzyl, R_(x) -phenyl, 2- or 3-furyl or -thienyl, 2-, 3- or 4-pyridyl;or therapeutically acceptable acid addition salts thereof.

The most preferred compounds of this invention are those of Formula II,wherein R is hydrogen, methyl, methoxy, fluoro, chloro ortrifluoromethyl in the 7 or 8-positions, x is the integer 1 or 2, y isthe integer 2 or 3, R" is hydroxy, methoxy, allyloxy, propargyloxy, oralkanoyloxy with 3 to 10 carbon atoms and R' is m- or p-R_(x) -phenyl;or therapeutically acceptable acid addition salts thereof.

The compounds of this invention are prepared according to conventionalmethods, for example by:

(a) condensing compounds of Formulae III and IV ##STR4## wherein one ofY and Z₂ is amino or imino respectively and the other is a reactivelyesterified hydroxy group. Said group is such esterified by a stronginorganic or organic acid, above all a hydrohalic acid, e.g.hydrochloric, hydrobromic or hydriodic acid; sulfuric or an aromaticsulfonic acid, e.g. p-toluene or p-bromobenzene sulfonic acid. Saidcondensation is preferably carried out in the presence of a basiccondensation agent, such as an alkali or alkaline earth metal hydroxide,carbonate or bicarbonate, e.g. sodium, potassium or calcium hydroxide orcarbonate, alkali metal hydrides, lower alkoxides or alkanoates, e.g.sodium hydride, methylate or acetate, as well as organic tertiarynitrogen bases, such as tri-lower alkylamines or pyridines, e.g.triethylamine or lutidine.

Another process for preparing the compounds of the invention consistsin:

(b) reducing a compound of Formula V ##STR5## wherein A is C_(m-1)H_(2m-2) -CO, C_(n) H_(2n-s) or Y'-C_(n) H_(2n-1), wherein Y' is areactively esterified hydroxy group, R₅ is hydrogen or R₁ + R₅ are anadditional C,C-bond, R'₄ is R₄ or HPh-lower alkanoyl and the symbolseach of r and s is the integer 0 or 2, but r + s = 2 or 4. The group Y'is preferably hydroxy esterified by a strong inorganic or organic acid,above all a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydriodicacid; sulfuric or an aromatic sulfonic acid, e.g. p-toluene orp-bromobenzene sulfonic acid. The reduction is carried out in the usualmanner, depending on the presence of ketonic and/or amidic carbonyl. Thelatter is preferably reduced with the use of simple or complex lightmetal hydrides, such as diborane or alkali metal boro- oraluminumhydrides or -alkoxyhydrides, e.g. lithium aluminumhydride and/orsodium trimethoxyborohydride. Said ketones or olefines are preferablyreduced with the use of catalytically activated or nascent hydrogen,e.g. hydrogen in the presence of palladium or platinum catalysts, orgenerated electrolytically, or preferably with cyanoborohydride. Finallythe reductive elimination of Y' is carried out by subjecting said esterto the hydride reducing agents mentioned above, preferably to lithiumaluminum hydride.

Another process for preparing the compounds of the invention consistsin:

(c) condensing a compound of Formula VI ##STR6## with R₄ -metalcompounds. Said compounds are preferably lithium or halomagnesium(Grignard) compounds, and the condensation is also performed in theusual manner, preferably in the presence of polar diluents, such as openor cyclic ethers, e.g. diethyl ether, tetrahydrofuran or dioxan.

Another process for preparing the compounds of Formula I consists in:

(d) ring-closing a compound of Formula VII ##STR7## wherein Y is areactively esterified hydroxy group. Said group is such esterified by astrong inorganic or organic acid, above all a hydrohalic acid, e.g.hydrochloric, hydrobromic or hydriodic acid; sulfuric or an aromaticsulfonic acid, e.g. p-toluene or p-bromobenzene sulfonic acid. Thering-closure is preferably carried out in the presence of a basiccondensation agent, such as an alkali or alkaline earth metal hydroxide,carbonate or bicarbonate, e.g. sodium, potassium or calcium hydroxide orcarbonate, alkali metal hydrides, lower alkoxides or alkanoates, e.g.sodium hydride, methylate or acetate, as well as organic tertiarynitrogen bases, such as tri-lower alkylamines or pyridines, e.g.triethylamine or lutidine.

The compounds of the invention so obtained can be converted into eachother according to known methods. Thus, for example, compounds with R₃being hydroxy, can be etherified or esterified in the usual manner, oralkali metal, e.g. lithium salts thereof, can be reacted with reactiveesters of lower alkanols or reactive alkanoic acid derivatives, such ashalides or anhydrides thereof. Resulting esters can be hydrolyzed bymethods known per se, preferably with aqueous alkalies. Moreover,phenols can be etherified with the use of diazoalkanes. Benzylethers mayalso be cleaved hydrogenolytically, e.g. in the presence of Pd- orPt-catalysts, which method may also be employed for dehalogenating Ph,or reducing a nitro group therein to amino. Nitration of Ph may also becarried out in the usual manner, for example by heating a resultingcompound with a mixture of fuming nitric acid and sulfuric acid oracetic anhydride, or a nitrate thereof in trifluoroacetic acid. An iodoatom in Ph may also be replaced by trifluoromethyl, for example byreacing the iodide with trifluoromethyl iodide in the presence of copperpowder.

Finally, the compounds of the invention are either obtained in the free,basic form, or as a salt thereof. Any resulting base can be convertedinto a corresponding acid addition salt, preferably with the use of atherapeutically useful acid or anion exchange preparation, or resultingsalts can be converted into the corresponding free bases, for example,with the use of a stronger base, such as a metal or ammonium hydroxide,basic salt or cation exchange preparation, e.g. an alkali metalhydroxide or carbonate. Said acid addition salts are preferably such oftherapeutically acceptable inorganic or organic acids, such as strongmetalloidic acids, for example hydrohalic, e.g. hydrochloric orhydrobromic or hydriodic acid; sulfuric, phosphoric, nitric orperchloric acid; aliphatic or aromatic carboxylic or sulfonic acids,e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic,phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic,salicylic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic,ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic,halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilicor cyclohexylsulfamic acid. These or other salts, for example, thepicrates, can also be used for purification of the bases obtained; thebases are converted into salts, the salts are separated and the basesare liberated from the salts. In view of the close relationship betweenthe free compounds and the compounds in the form of their salts,whenever a compound is referred to in this context, a corresponding saltis also intended, provided such is possible or appropriate under thecircumstances.

The starting material of Formulae III to VIII is new, but can beprepared according to known procedures, e.g. those illustrated in theexamples herein.

Compounds of Formula III can easily be obtained by reducing thecorresponding 1-benzofuran- or 1,4-benzodioxan-2-yl-alkanoic acid to thecorresponding alcohol with lithium aluminum hydride or sodium2-methoxyethoxyaluminum hydride, and reactively esterifying it with astrong acid or its derivative mentioned above. The reactive esters maybe reacted with ammonia in an organic solvent, such as ethanol orbenzene, preferably under raised pressure and temperature, to yield theamines.

Compounds of Formula V are either obtained from the previous acids byconverting them into a halide, mixed anhydride or amide of imidazole,and reacting them with the corresponding piperidines. The unsaturatedcompounds are preferably enamines prepared from the correspondingaldehydes and said piperidines, and the aldehydes are obtained byreduction of said acid halides according to Rosenmund, or of theirnitriles with diisobutylaluminum hydride. Finally the alcoholscorresponding to compounds V with A = Y'-C_(n) H_(2n-1) are prepared bycondensing the corresponding 1-benzofuran- or1,4-benzodioxan-2-yl-alkyleneoxides with said piperidines, or byreaction of the a-bromoketone followed by reduction with sodiumborohydride; they are disclosed in U.S. Pat. No. 3,914,238. Saidalcohols are reactively esterified in the usual manner, either with theacids HY' under anhydrous conditions, e.g. in the presence of sulfuricacid, or with halides or anhydrides of said acids, e.g. tosyl chloride.

Finally the compounds of Formula VII are prepared by theMannich-reaction of said piperidines with corresponding aldehydes and/orketones, brominating the resulting piperidinoalkanones, condensing theα-bromoketones obtained with mono-acetylcatechol, reducing the ketoniccondensation product with sodium borohydride to the correspondingalcohol and esterifying it as mentioned under item a).

In case mixtures of geometrical or optical isomers of the compounds ofFormulae I to VII are obtained, these can be separated into the singleisomers by methods in themselves known, e.g. by fractional distillation,crystallization and/or chromatography. Racemic products can likewise beresolved into the optical antipodes, for example, by separation ofdiastereomeric salts thereof, e.g. by fractional crystallization of d-or 1-tartrates or α-methylbenzylammonium salts.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures, preferably atthe boiling point of the solvents used, at atmospheric orsuperatmospheric pressure.

The invention further includes any variant of the present process, inwhich an intermediate product obtainable at any stage of the process isused as a starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of their salts or opticallypure antipodes. Mainly those starting materials should be used in saidreactions, that lead to the formation of those compounds indicated aboveas being especially valuable, e.g. those of Formula II.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with (a)diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, celluloseand/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol, for tablets also(c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, if desired, (d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, enzymes of the binders oreffervescent mixtures and/or (e) absorbents, colorants, flavors andsweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories are advantageously preparedfrom fatty emulsions or suspensions. Said compositions may be sterilizedand/or contain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing; granulating or coating methodsrespectively and contain about 0.1 to 75%, preferably about 1 to 50%, ofthe active ingredient.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade, and all parts wherever given are parts by weight.If not mentioned otherwise, all evaporations are performed under reducedpressure, preferably between about 15 and 100 mm Hg.

The compounds listed in the table of Example 8 are the following: 1-3)2-[2-(4-hydroxy-4-[p-tolyl, p-methoxyphenyl orp-fluorophenyl]-piperidino)-ethyl]-1,4-benzodioxan; 4)7-chloro-2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan;5-6) 2-[-(4-hydroxy-4-[benzyl orp-chlorophenyl]-peperidino)-ethyl]-1,4-benzodioxan; 7-11) 8-methyl-,7-methyl-, 8-methoxy-, 6,7-dichloro- or6,7,8-trichloro-2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan;12-16) 2-[2-(4-hydroxy-4-[t-butyl, 2-pyridyl, 3-pyridyl,p-chloro-m-trifluorophenyl or1-benzothien-2-yl]-piperidino)-ethyl]-1,4-benzodioxan; 17)2-[2-(4-phenylpiperidino)-ethyl]-1,4-benzodioxan and 18)2-[2-(4-methoxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan in the formof the various salts shown in the "Salt"-column, or as free bases (No.4, 10 and 16).

EXAMPLE 1

The mixture of 6.68 g of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 3.54 g of4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100ml of 4-methyl-2-pentanone is refluxed 48 hours. It is filtered,evaporated and the residue recrystallized from isopropanol, to yield the2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan melting at142°.

It is suspended in 20 ml of ethanol, the suspension neutralized withethanolic hydrogen chloride and the precipitate recrystallized fromethanol-diethyl ether, to yield the corresponding hydrochloride meltingat 203°.

Analogously the 2-(4-hydroxy-4-phenylpiperidinomethyl)-1,4-benzodioxanhydrochloride is prepared, melting after recrystallization from methanolat 215°-217°.

The starting material is prepared as follows: The solution of 16 g ofbromine in 10 ml of petroleum ether is slowly added to the solution of6.7 g of allyl cyanide in 30 ml of the same solvent, while stirring andkeeping the temperature at about -15°. After removal of the solvent theoily 3,4-dibromo-butyronitrile is obtained in quantitative yield[J.A.C.S. 67, 400 (1945)]

227 g thereof are added dropwise in 5 equal parts (45, 4 g) to thestirred mixture of 85 g of catechol and 50 g of anhydrous potassiumcarbonate in 100 ml of refluxing acetone each. Another 50 g of potassiumcarbonate are added, followed by a slow addition of the second part ofnitrile. After 3 more cycles, using 40 g of potassium carbonate with onepart nitrile each, and sufficient acetone to allow stirring, the mixtureis refluxed for 20 hours. It is filtered, the filtrate evaporated, theresidue distilled and the fraction boiling at 105°/0.15 mm Hg collected,to yield the 1,4-benzodioxan-2-yl-acetonitrile (Belgium Pat. No.643,853 - Aug. 14, 1964).

The mixture of 111 g thereof 63.5 ml of sulfuric acid, 160 ml of aceticacid and 160 ml of water is refluxed for 48 hours. It is poured on ice,the resulting solid collected and recrystallized from benzene-petroleumether to yield the 1,4-benzodioxan-2-yl-acetic acid melting at 100°(Belgium Pat. No. 613,211 - July 30, 1962).

The solution of 5.8 g thereof in 100 ml of benzene is added dropwise to16.5 ml of a refluxing, 70% benzene solution of sodiumbis(2-methoxyethoxy)-aluminum hydride under nitrogen. When addition iscomplete, the mixture is refluxed for 4 hours, cooled and poured slowlyinto 20 ml of 25% sulfuric acid. After filtration and removal of thesolvent, the residue is taken up in methylene chloride, the solutionwashed several times with saturated aqueous sodium bicarbonate, driedand evaporated, to yield the oily 2-(2-hydroxyethyl)-1,4-benzodioxan.

The mixture of 3.6 g thereof, 5.7 g of p-toluenesulfonyl chloride and 20ml of dry pyridine is stirred and cooled in an ice bath for 2 hours. Iceis then added to the mixture, the resulting solid is filtered off andrecrystallized from ethyl acetate-petroleum ether, to yield the2-(2-tosyloxyethyl)-1,4-benzodioxan melting at 82°-3°.

According to the above method the other intermediates for the compoundsof Formula II, listed in the table of Example 8, are prepared fromequivalent amounts of the corresponding starting materials and theirmelting points are shown in the last column of said table.

EXAMPLE 2

The solution of 5.5 g of1-[2-(ρ-1,4-benzodioxan-2-yl)acetyl]-4-hydroxy-4-phenylpiperidine in 50ml of tetrahydrofuran is added to the cooled and stirred suspension of1.2 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. It isstirred at room temperature overnight and decomposed with a few drops ofethyl acetate, 1.2 ml of water, 1.2 ml of 15% aqueous sodium hydroxideand 3.6 ml of water. The mixture is filtered, the filtrate evaporatedand the residue recrystallized from isopropanol, to yield theρ-2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan melting at141°-143°; [α]_(D) = -44.8° (methanol). The hydrochloride thereof meltsat 255°-227°; [α]_(D) = -36.5° (methanol).

In the same manner the d-base is obtained, melting at 141°-143°; [α]_(D)= +44.8° (methanol) and its hydrochloride melts at 225°-227°; [α]_(D) =+36.5° (methanol).

The starting material is prepared as follows: 19.4 g of1,4-benzodioxan-2-yl-acetic acid and 12.1 g of d- α-methylbenzylamineare dissolved in 100 ml of hot isopropanol. After standing overnight,the salt formed is filtered off and recrystallized five times fromisopropanol. Experiments show that this is sufficient to opticallyresolve said acid. It is liberated with diluted hydrochloric acid, themixture extracted with diethyl ether and the extract evaporated, toyield the d-1,4-benzodioxan-2-yl-acetic acid with [α]_(D) = +49°(ethanol).

In like manner, using ρ-α-methylbenzylamine, the antipode acid isobtained, [α]_(D) =]-49° (ethanol).

The solution of 3 g of said ρ-acid in 20 ml of tetrahydrofuran isstirred with 3 g of carbonyldiimidazole for 1 hour. Then 2.75 g of4-hydroxy-4-phenylpiperidine, suspended in 20 ml tetrahydrofuran areadded and the mixture stirred overnight. It is evaporated, the residuedissolved in ethyl acetate and the solution washed with dilute aqueoushydrochloric acid and aqueous sodium hydroxide, dried and evaporated, toyield the1-[2-(ρ-1,4-benzodioxan-2-yl)-acetyl]-4-hydroxy-4-phenylpiperidine.

EXAMPLE 3

The solution of 5 g of1-[3-(1,4-benzodioxan-2-yl)propionyl]-4-hydroxy-4-phenylpiperidine in 50ml of tetrahydrofuran is added to the stirred mixture of 2 g of lithiumaluminum hydride and 50 ml of tetrahydrofuran at room temperature.Stirring is continued for 12 hours, whereupon the reaction mixture isdecomposed with a few drops of ethyl acetate, 2 ml of water, 4 ml of 15%aqueous sodium hydroxide and 4 ml of water. It is filtered, the filtrateevaporated and the residue recrystallized from isopropanol, to yield the2-[3-(4-hydroxy-4-phenylpiperidino)propyl]-1,4-benzodioxan melting at95°-98°. The hydrochloride thereof is prepared in the above illustratedmanner and recrystallized from isopropanol, mp. 155°-157°.

The starting material is prepared as follows: The mixture of 10 g of2-(2-tosyloxyethyl)-1,4-benzodioxan, 2.4 g of sodium cyanide, 4 ml ofwater and 20 ml of ethanol is refluxed for 48 hours. It is evaporated,the residue taken up in water and extracted with diethyl ether. Theextract is dried, evaporated and 5 g of the crude nitrile stirred andrefluxed for 48 hours in a mixture of 2.8 ml of sulfuric acid, 7.2 ml ofwater and 7.2 ml of acetic acid. The mixture is poured into ice water,extracted with diethyl ether, the extract washed with water andre-extracted with aqueous sodium bicarbonate. The alkaline solution ismade acidic with hydrochloric acid and extracted with diethyl ether. Theextract is dried, evaporated, 2.5 g of the crude acid are dissolved in25 ml of tetrahydrofuran and the solution treated with 3 g ofcarbonyldiimidazole for 30 minutes while stirring. 2.5 g of4-hydroxy-4-phenylpiperidine are added and the mixture is stirredovernight. It is evaporated, the residue dissolved in ethyl acetate, thesolution washed with dilute aqueous sodium hydroxide and hydrochloricacid, dried and evaporated, to yield the1-[3-(1,4-benzodioxan-2-yl)-propionyl]-4-hydroxy-4-phenylpiperidine.

EXAMPLE 4

To the solution of 1.9 g of thiophene in 25 ml of tetrahydrofuran 16 mlof 1.6 N butyl lithium in hexane are added dropwise while stirring at-75° under nitrogen. After 15 minutes the solution of 4.0 g of2-[2-(4-oxopiperidino)-ethyl]-1,4-benzodioxan in 25 ml oftetrahydrofuran is added dropwise while stirring and the mixture isallowed to warm up to room temperature. It is combined with 10 ml ofsaturated aqueous ammonium chloride, the organic layer separated,evaporated and the residue recrystallized from isopropanol, to yield the2-[2-(4-hydroxy-4-thienyl-2-piperidino)-ethyl]-1,4-benzodioxan meltingat 117°-118°.

The starting material is prepared as follows: The mixture of 10 g of2-(2-tosyloxyethyl)-1,4-benzodioxan, 10 g of 4-piperidone hydrochloride,20 g of anhydrous sodium carbonate and 160 ml of dimethylformamide isstirred vigorously at room temperature for 48 hours. It is filtered, theresidue washed with a small amount of dimethylformamide and the filtrateevaporated. The residue is dissolved in ethyl acetate, the solutionextracted with hydrochloric acid, the extract made alkaline with 50%aqueous sodium hydroxide while cooling and re-extracted with methylenechloride. The latter extract is dried and evaporated, to yield the2-[2-(4-oxopiperidino)-ethyl]-1,4-benzodioxan, which solidifies onstanding.

EXAMPLE 5

The mixture of 4.6 g of 2-(2-tosyloxyethyl)-2,3-dihydrobenzofuran, 2.64g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonateand 100 ml of 4-methyl-2-pentanone is refluxed for 48 hours. It isfiltered, evaporated and the residue recrystallized fromisopropanol-petroleum ether, to yield the2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-2,3-dihydrobenzofuran meltingat 107°.

It is suspended in ethanol, neutralized with ethanolic hydrogen chlorideand the precipitate recrystallized from ethanoldiethyl ether, to yieldthe corresponding hydrochloride melting at 185°-187°.

The starting material is prepared as follows: The solution of 14.2 g of2-(2,3-dihydrobenzofuran-2-yl)-acetic acid [Gazz. Chim. Ital. 93, 52(1963)] in 100 ml of tetrahydrofuran is added dropwise to the suspensionof 4.55 g of lithium aluminum hydride in 200 ml of tetrahydrofuran whilestirring. The mixture is refluxed for 18 hours, then cooled in anice-bath and decomposed by adding 4.5 ml of water, 4.5 ml 15% aqueoussodium hydroxide and 14.6 ml of water. It is filtered, evaporated andthe residue taken up in ethyl acetate. The solution is washed withaqueous sodium bicarbonate, water and saturated aqueous sodium chloride,dried, evaporated and the residue distilled in a kugelrohr at 140°/0.1mmHg, to yield the 2-(2-hydroxyethyl)-2,3-dihydrobenzofuran.

The stirred mixture of 10 g thereof, 17.4 g of p-toluene sulfonylchloride and 30 ml of pyridine is cooled in an ice-bath for 2 hours. Iceis then added to the mixture, the resulting solid filtered off andrecrystallized from ethyl acetate-petroleum ether, to yield the2-(2-tosyloxyethyl)-2,3-dihydrobenzofuran melting at 51°-54°.

EXAMPLE 6

The mixture of 2 g of2-[2-(4-hydroxy-4-phenylpiperidino)ethyl]-1,4-benzodioxan hydrochloride,4 ml of propionic anhydride and 4 ml of pyridine is stirred and refluxedfor 10 minutes. It is diluted with diethyl ether, the semi-solidfiltered off, washed with diethyl ether and recrystallized fromisopropanol-diethyl ether, to yield the2-[2-(4-propionyloxy-4-phenylpiperidino)-ethyl]1,4-benzodioxanhydrochloride melting at 170° with decomposition.

EXAMPLE 7

To the stirred solution of 3.0 g of2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxane in 50 ml oftetrahydrofuran is added 8 ml of 1.6N butyl lithium in hexane. After 3hours the solution of 2.4 g of n-decanoyl chloride in 10 ml oftetrahydrofuran is added, the mixture is refluxed for 48 hours andtreated with 10 ml of saturated aqueous ammonium chloride. The organicphase is separated, evaporated and the residue chromatographed on silicagel plates using chloroform-ethylacetate (4:1) as the developingsolvent. The material at R_(cm) =4.5 is collected and the analyticallypure 2-[2-(4-n-decanoyloxy-4-phenylpiperidinoethyl]-1,4-benzodioxane isa light yellow oil. It may be dissolved in sesame oil for injection toprovide a long-acting drug-effect.

EXAMPLE 8

According to the methods illustrated by the preceeding examples,indicated in the table below (Ex.), the following compounds of FormulaII are prepared from equivalent amounts of the corresponding startingmaterials: y = 2, Starting Material m.p. of tosylates:

    __________________________________________________________________________                                         Start. Mat.                              No.                                                                              R    X R'       R"  Salt  m.p. ° C                                                                    Ex.                                                                              m.p. ° C                          __________________________________________________________________________    1  H    1 4-CH.sub.3 --C.sub.6 H.sub.4                                                           OH  HCl   190  3  --                                       2  H    1 4-CH.sub.3 O--C.sub.6 H.sub.4                                                          "   "     155  3  --                                       3  H    1 4-F--C.sub.6 H.sub.4                                                                   "   HBr   235  3  --                                       4  7-Cl 1 C.sub.6 H.sub.5                                                                        "   --    135-8                                                                              3  --                                       5  H    1 benzyl   "   HCl   214  1  --                                       6  H    1 4-Cl--C.sub.6 H.sub.4                                                                  "   CH.sub.3 SO.sub.3 H                                                                 184-5                                                                              1  82-3                                     7  8-CH.sub.3                                                                         1 C.sub.6 H.sub.5                                                                        "   HCl   202-3                                                                              1  160/0.1 mm                               8  7-CH.sub.3                                                                         1 "        "   "     225  1  56-8                                     9  8-OCH.sub.3                                                                        1 "        "   "     199-O                                                                              1  64-6                                     10 6,7-Cl                                                                             2 "        "   --    225-227                                                                            1  --                                       11 6,7,8-Cl                                                                           3 "        "   HCl   I.R.*                                                                              1  --                                       12 H    1 C(CH.sub.3).sub.3                                                                      "   CH.sub.3 SO.sub.3 H                                                                 182-5                                                                              4  --                                       13 H    1 2-pyridyl                                                                              "   2HCl  260-2                                                                              4  --                                       14 H    1 3-pyridyl                                                                              "   "     245-O                                                                              4  --                                       15 H    1 3-CF.sub.3 -4-Cl--C.sub.6 H.sub.3                                                      "   HCl   219-O                                                                              4  MgBr                                     16 H    1 1-benzothi-                                                                            "   --    175-8                                                                              4  --                                                 enyl-2                                                              17 H    1 C.sub.6 H.sub.5                                                                        H   HCl   224-5                                                                              1  82-3                                     18 H    1 "        OCH.sub.3                                                                         "     247  3  --                                       __________________________________________________________________________     *3580, 1280 and 1033 cm.sup.-1.                                          

The preparation of various new starting materials is illustrated asfollows: The solution of 48.6 g of2-(7-methyl-1,4-benzodioxan-2-yl)-acetic acid in the minimum amount oftetrahydrofuran is added dropwise at reflux rate to the stirredsuspension of 13.4 g of lithium aluminum hydride in 200 ml drytetrahydrofuran. The mixture is refluxed overnight, cooled, anddecomposed by the addition of 13.4 ml of water, 13.4 ml 15% aqueoussodium hydroxide and 40 ml of water. It is filtered, evaporated, theresidue distilled in a molecular still, and the fraction boiling at155°-165°/0.1 mm Hg collected as colorless oil, to yield the2-(2-hydroxyethyl)-7-methyl-1,4-benzodioxan.

To the Grignard reagent, prepared from 3.6 g of magnesium and 18.9 g ofbenzyl bromide in 50 ml of diethyl ether, the solution of 18.4 g of1-benzyl-4-piperidine in 100 ml of diethyl ether is added and themixture refluxed for one hour. It is decomposed with 30 ml of saturatedaqueous ammonium chloride, the ethereal solution separated, dried andevaporated, leaving a thick oil. 26 g thereof are hydrogenated in amixture of 120 ml of ethanol and 120 ml of acetic acid over 3 g of 10%palladium on carbon at 3 at. and 50° until one molar equivalent ofhydrogen has been taken up. It is filtered, the filtrate evaporated, theresidue treated with ammonium hydroxide and extracted with methylenechloride. The extract is dried and evaporated, to yield the4-benzyl-4-hydroxy-piperidine, which is pure enough for furtherreaction.

Analogously the 4-hydroxy-4-(4-methoxyphenyl)-piperidine is obtained,melting after recrystallization from isopropanol-petroleum ether at121°-223°.

To the stirred solution of 11.64 g of 2-(1,4-benzodioxan-2-yl)-aceticacid in 60 ml of tetrahydrofuran is added 12 g of1,1-carbonyldiimidazole. After the evolution of carbon dioxide hasceased, 10.6 g of 4-hydroxy-4-phenylpiperidine are added and the mixturestirred overnight at room temperature. It is evaporated, the residuetaken up in ethyl acetate, the solution washed with water, Nhydrochloric acid and water, dried and evaporated, to yield the1-[2-(1,4-benzodioxan-2-yl)-acetyl]-4-hydroxy-4-phenylpiperidine.

EXAMPLE 9

To the solution of 20 g of2-[2-(4-hydroxy-4-phenylpiperidino)-1-tosyloxyethyl]-1,4-benzodioxan in500 ml of tetrahydrofuran is added 7 g of lithium aluminum hydride andthe mixture stirred and refluxed for 6 hours. It is treated with 2 ml ofethyl acetate, 7 ml of water, 7 ml of 15% aqueous sodium hydroxide and22 ml of water while stirring. The inorganic residue is filtered off,the filtrate evaporated and the residue treated with ethanolic hydrogenchloride, followed by recrystallization from ethanol-diethyl ether, toyield the 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]1,4-benzodioxanhydrochloride melting at 203°.

The starting material is prepared as follows: To the solution of 42 g of2-(2-bromoacetyl)-1,4-benzodioxan in 360 ml of methanol, 12 g of sodiumborohydride are added while stirring and keeping the temperature below10°. After five hours, the mixture is cooled to 0° and 13.2 g of sodiumhydroxide in 150 ml of methanol are added and the mixture kept at -15°overnight. It is poured onto ice, extracted with diethyl ether, theextract washed with saturated aqueous sodium chloride, dried andevaporated, to yield the 1,4-benzodioxan-2-yl-ethyleneoxide.

The mixture of 7.1 g thereof and 3.54 g of 4-hydroxy-4-phenylpiperidinein 75 ml of isopropanol is refluxed for 5 hours and evaporated. Theresidue is dissolved in ethyl acetate and the solution extracted withaqueous methanesulfonic acid. The substituted piperidine distributesitself between the aqueous and organic layer. Evaporation of the organiclayer gives a gummy residue which slowly crystallizes. Afterrecrystallization from isopropanol, the2-[2-(4-hydroxy-4-phenylpiperidino)-1-hydroxyethyl]-1,4-benzodioxanmethanesulfonate melts at 208°-210°. The aqueous extract is made basicwith ammonium hydroxide, extracted with methylene chloride, the organicphase dried and evaporated and the residue is recrystallized fromisopropanol-petroleum ether, to yield the corresponding free basemelting at 95°.

To the solution of 20 g thereof in 80 ml of pyridine is added withcooling and stirring in an ice bath 11.8 g of p-toluenesulfonyl chloridein portions. After standing 3 hours in the ice bath, the mixture isadded to 200 g of ice water, the aqueous phase is decanted from thecrude solid and the residue is washed several times with water, filteredand dried, to yield the2-[2-(4-hydroxy-4-phenylpiperidino)-1-tosyloxyethyl]-1,4-benzodioxan.

EXAMPLE 10

To the solution of 10 g of 1,4-benzodioxan-2-yl-acetaldehyde and 12.7 gof 4-hydroxy-4-phenylpiperidine in 300 ml of methanol is added 8 ml of4.5 N ethanolic hydrogen chloride at which conditions the2-[2-(4-hydroxy-4-phenylpiperidino)-vinyl]-1,4-benzodioxan is formed insitu. After standing for one hour, at room temperature the solution of2.4 g of sodium cyanoborohydride in 30 ml of methanol is added dropwisewhile stirring. After one hour the solution is made strongly basic withaqueous sodium hydroxide, concentrated to a small volume and dilutedwith water. The mixture is extracted with ethyl acetate, the extractdried and evaporated. The residue is treated with ethanolic hydrogenchloride and the precipitate recrystallized from ethanoldiethyl ether,to yield the 2-[2-(4-hydroxy-4-phenylpiperidino)ethyl]-1,4-benzodioxanhydrochloride melting at 203°.

The starting material is prepared as follows: To the solution of 20 g of1,4-benzodioxan-2-yl-acetonitrile in 200 ml of benzene is added dropwise71 ml of a 1.6 N solution of diisobutyl aluminum hydride in benzenewhile stirring at 10°. After 6 hours 50 ml of methanol are added,followed by 200 ml of water. The organic layer is separated, dried andevaporated, to yield the 1,4-benzodioxan-2-yl-acetaldehyde.

EXAMPLE 11

To a solution of 7 g of sodium methoxide in 200 ml of methanol, 20 g of1-[4-(2-acetoxyphenoxy)-3-tosyloxybutyl]-4-hydroxy-4-phenylpiperidineare added, the mixture refluxed for 6 hours and concentrated to a smallvolume. It is diluted with water, extracted with methylene chloride, theextract dried and evaporated. The residue is treated with ethanolichydrogen chloride and the precipitate recrystallized several times fromethanoldiethyl ether, to yield the2-[2-(4-hydroxy-4-phenylpiperidino)ethyl]-1,4-benzodioxan hydrochloridemelting at 203°.

The starting material is prepared as follows: The solution of 20 g of4-hydroxy-4-phenylpiperidine hydrochloride, 10 ml of acetone, 5.6 g ofparaformaldehyde and 100 ml of nitromethane is refluxed for 12 hours. Itis diluted with 500 ml of cyclohexane and the precipitate collected, toyield the 4-(4-hydroxy-4-phenypiperidino)-2-butanone hydrochloride.

To the vigorously stirred suspension of 20 g thereof in 100 ml of aceticacid is added dropwise the solution of 3.7 ml bromine in 25 ml of aceticacid while keeping the temperature at 25°. After 1 hour the brominecolor has completely disappeared, whereupon about half of the aceticacid is distilled off. The concentrate is diluted with diethyl ether andthe precipitate collected, to yield the1-bromo-4-(4-hydroxy-4-phenylpiperidino)-2-butanone hydrochloride.

To the ice cooled suspension of 10 g of 56% sodium hydride in mineraloil and 100 ml of dimethylformamide is added slowly in sucession withstirring, 16 g of o-acetylcatechol followed by 20 g of saidhydrochloride. After stirring the mixture for 12 hours at 5°, 2 g ofsodium borohydride are added and the temperature is allowed to rise toroom temperature. After one hour, the mixture is poured onto ice andextracted with methylene chloride. The extract is dried and evaporated,to yield the1-(2-acetoxyphenoxy)-4-(4-hydroxy-4-phenylpiperidino)-2-butanol as anoil. To the solution of 20 g thereof in 70 ml of pyridine, cooled in anice bath, is added in portions with stirring 10 g of p-toluenesulfonylchloride. After 3 hours the mixture is diluted with 500 ml of ice water,the solid is separated, washed several times with water and dried overphosphorus pentoxide, to yield the1-[4-(2-acetoxyphenoxy)-3-tosyloxybutyl]-4-hydroxy-4-phenylpiperidine.

EXAMPLE 12

To the solution of 5 g of2-[2-(4-phenyl-1,2,5,6-tetrahydropyridyl-1)ethyl]-1,4-benzodioxanhydrochloride in 100 ml of acetic acid-water (9:1) is added 0.5 g of 10%palladium on carbon and the mixture hydrogenated at 3 at. until oneequivalent of hydrogen has been absorbed. The mixture is filtered, thefiltrate evaporated, the residue taken up in water and the mixture madebasic with ammonium hydroxide. It is extracted with methylene chloride,the extract dried and evaporated. The residue is taken up in isopropanoland the solution acidified with ethanolic hydrogen chloride, to yieldthe 2-[2-(4-phenylpiperidino)-ethyl]-1,4-benzodioxan hydrochloridemelting at 224° to 225°; it is identical with compound No. 17 of Example8.

The starting material is prepared according to the method described inExample 1, it melts at 200°-201°.

EXAMPLE 13

To the solution of 5 g of2-[2-(4-benzoylpiperidino)ethyl]-1,4-benzodioxan hydrobromide in 100 mlof 90% aqueous acetic acid is added 1 g of 10% palladium on carbon andthe mixture hydrogenated at 3 at. and 50° until two molar equivalent ofhydrogen have been absorbed. It is filtered, the filtrate evaporated,the residue taken up in water, the mixture made basic with ammoniumhydroxide and extracted with methylene chloride. The extract is dried,evaporated, the residue neutralized with ethanolic hydrogen chloride andthe solids collected, to yield the2-[2-(4-benzylpiperidino)-ethyl]-1,4-benzodioxan hydrochloride showingin the I.R.-spectrum bands at 2447 and 748cm⁻¹.

The starting material is prepared analogous to the method illustrated byExample 1, it melts at 193°-195°. Analogously the2-[2-(4-p-fluorobenzoylmethylpiperidino)-ethyl]-1,4-benzodioxanhydrochloride, m.p. 165°-166°, is hydrogenated, to yield the2-[2-(4-p-fluorophenethylpiperidino)-ethyl]-1,4-benzodioxanhydrochloride showing I.R.-bands at 2485 and 695cm⁻¹.

EXAMPLE 14

Preparation of 10,000 tablets each containing 5 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      ______________________________________                                        2-[2-(4-hydroxy-4-phenylpiperidino)-                                          ethyl]-1,4-benzodioxan hydrochloride                                                                  50.00    g                                            Lactose                 1,157.00 g                                            Corn starch             75.00    g                                            Polyethylene glycol 6,000                                                                             75.00    g                                            Talcum powder           75.00    g                                            Magnesium stearate      18.00    g                                            Purified water          q.s.                                                  ______________________________________                                    

Procedure:

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance, lactose, talcum, magnesium stearate and half ofthe starch are mixed in a suitable mixer. The other half of the starchis suspended in 40 ml of water and the suspension added to the boilingsolution of the polyethylene glycol in 150 ml of water. The paste formedis added to the powders which are granulated, if necessary, with anadditional amount of water. The granulate is dried overnight at 35°,broken on a screen with 1.2 mm openings and compressed into tabletsusing concave punches with 6.4 mm diameter, uppers bisected.

Preparation of 10,000 capsules each containing 2.5 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      ______________________________________                                        ρ-2-[2-(4-hydroxy-4-phenylpiperidino)-                                    ethyl]-1,4-benzodioxan hydrochloride (α=-36.5°)                                            25.0    g                                           Lactose                   1,875.0 g                                           Talcum powder             100.0   g                                           ______________________________________                                    

Procedure:

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance is placed in a suitable mixer and mixed firstwith the talcum, then with the lactose until homogeneous. No. 3 capsulesare filled with 200 mg each, using a filling machine.

Analogously tablets and hard gelatin capsules of the other compoundsdescribed in the previous examples are prepared.

EXAMPLE 15

The mixture of 2.2 g of2-[2-(4-hydroxy-4-pyridyl-2-piperidino)-ethyl]-1,4-benzodioxanhydrochloride, 4 ml of pyridine and 4 ml of propionic anhydride isstirred and refluxed for 20 minutes. It is diluted with diethyl etherand the precipitate recrystallized from isopropanol, to yield the2-[2-(4-propionyloxy-4-pyridyl-2-piperidino)-ethyl]-1,4-benzodioxanhydrochloride melting at 125°-130° with decomposition.

EXAMPLE 16

To the stirred solution of 4.0 g of2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan in 50 ml ofanhydrous tetrahydrofuran is added 9.5 ml of 1.6 N n-butyl lithium inhexane at 0°. After warming the mixture up to room temperature, thesolution of 1.5 ml of pivaloyl chloride in 10 ml of tetrahydrofuran isadded while stirring and the whole is refluxed for 24 hours. Aftercooling 10 ml of saturated aqueous ammonium chloride are added, followedby 200 ml of diethyl ether. The organic layer is separated, washed withwater, dried evaporated and the residue dissolved in isopropanol. Thesolution is made acidic with 6N ethanolic hydrogen chloride and theprecipitate collected, to yield the2-[2-(4-pivaloyloxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxanhydrochloride melting at 195°-200° with decomposition.

EXAMPLE 17

To the stirred mixture of 1.44 g of lithium aluminum hydride in 150 mlof anhydrous tetrahydrofuran is added the solution of 14 g of1-[2-(1,4-benzoxathian-2-yl)-acetyl]-4-hydroxy-4-phenylpiperidine in 140ml of tetrahydrofuran. After stirring the mixture at room temperatureovernight, 1.4 ml of water, 2.9 ml of 15% aqueous sodium hydroxide and2.9 ml of water are added, the salts are filtered off and the filtrateis evaporated. The residue is taken up in 10 ml of hot isopropanol andthe solution treated with 4.5 g of cyclohexyl sulfamic acid and oncooling, the 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzoxathiancyclamate crystallizes, it melts at 176°.

The starting material is prepared as follows: To the stirred, refluxingsolution of 21 g of 2-hydroxy-thiophenol in 290 ml of acetone is addeddropwise 12.5 g of 3,4-dibromo-butyronitrile along with small portionsof 15.8 g of anhydrous potassium carbonate. After 30 minutes, the doubleaddition procedure with said amounts of dibromo compound and potassiumcarbonate is repeated, and after a further 30 minutes said procedure isrepeated a third time. The mixture is then refluxed for 20 hours,cooled, filtered, the residual salts washed with acetone, and thefiltrate evaporated. The residue is distilled (bulb to bulb), and thefraction boiling at 185°/0.5 mm Hg collected, to yield the2-(1,4-benzoxathian-2-yl)-acetonitrile.

The mixture of 50 g thereof, 74 ml of water, 74 ml of acetic acid and28.6 ml of sulfuric acid is refluxed for 48 hours. After cooling it isextracted 3 times with 150 ml of benzene each, the extract is washedwith aqueous sodium bicarbonate, and the aqueous phase acidified withhydrogen chloride. It is extracted with diethyl ether, the extract driedand evaporated, to yield the 2-(1,4-benzoxathian-2-yl)-acetic acid.

To the stirred solution of 10 g thereof in 45 ml of anhydroustetrahydrofuran is added 9.2 g of carbonyl-diimidazole followed after 30minutes by 10.1 g of 4-hydroxy-4-phenylpiperidine and stirring iscontinued for 24 hours. The mixture is evaporated, the residue taken upin ethyl acetate, the solution washed with water and dilutedhydrochloric acid, dried and evaporated, to yield the1-[2-(1,4-benzoxathian-2-yl)-acetyl]-4-hydroxy-4-phenylpiperidine.

In the analogous manner the2-[2-(4-phenylpiperidino)-ethyl]-1,4-benzoxathian cyclamate is prepared,melting at 146°-148°.

EXAMPLE 18

The solution of 3.55 g of2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzoxathian in 10 ml ofdioxan and 10 ml of methanol is added dropwise to the stirred solutionof 2.67 g of sodium metaperiodate in 20 ml of water. After 2 hoursstirring at room temperature the mixture is evaporated and the residuetaken up in methylene chloride. The solution is dried, evaporated and2.3 g of the residue dissolved in the minimum amount of ethanol. Thesolution is combined with that of 1.45 g of cyclohexyl sulfamic acid inethanol and the precipitate formed collected, to yield the correspondingS-oxide cyclamate melting at 158°-160°.

EXAMPLE 19

The solution of 4.9 g of1-[3-(1,4-benzodioxan-2-yl)-acetyl]-4-ethoxy-4-phenylpiperidine in 50 mlof tetrahydrofuran is added to the stirred mixture of 0.7 g of lithiumaluminum hydride and 100 ml of tetrahydrofuran at room temperature.Stirring is continued overnight, whereupon the reaction mixture isdecomposed with a few drops of ethyl acetate, 0.7 ml of water, 1.4 ml of15% aqueous sodium hydroxide and 2.1 ml of water. It is filtered, thefiltrate evaporated and 5 g of the residue taken up in the minimumamount of ethanol. The solution is combined with that of 1.7 g of maleicacid in ethanol, the mixture cooled, filtered and the residuerecrystallized from ethanol, to yield the2-[2-(4-ethoxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan maleatemelting at 160°-162°.

The starting material is prepared as follows: To the solution of 3.3 gof 1,4-benzodioxan-2-yl-acetic acid in 30 ml of tetrahydrofuran, 3.1 gof 1,1'-carbonyldiimidazole are added while stirring followed, after 30minutes, by 3.5 g of 4-ethoxy-4-phenylpiperidine in 30 ml oftetrahydrofuran. The mixture is stirred for 18 hours at roomtemperature, evaporated and the residue taken up in ethyl acetate. Thesolution is washed with water, N hydrochloric acid and saturated aqueoussodium chloride, dried and evaporated, to yield the1-(1,4-benzodioxan-2-yl-acetyl)-4-ethoxy-4-phenylpiperidine.

EXAMPLE 20

The mixture of 5 g of2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-benzofuran, 100 ml of aceticacid and 1 g of 10% platinum on charcoal is hydrogenated at 3 atm. androom temperature until the theoretical amount of hydrogen has beenabsorbed. It is filtered, the filtrate evaporated, the residue taken upin water, the mixture basified with 2N aqueous sodium hydroxide andextracted with methylene chloride. The extract is dried, evaporated andthe residue taken up in ethanol. The solution is neutralized withethanolic hydrogen chloride and the precipitate recrystallized fromethanol-diethyl ether, to yield the2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-2,3-dihydrobenzofuranhydrochloride melting at 185°-187°; it is identical with that obtainedaccording to Example 5.

The starting material is prepared as follows: The mixture of 16 g of2-acetyl-benzofuran, 4.8 g of sulfur and 13.2 ml of morpholine isrefluxed for 8 hours. Thereupon 160 ml of 10% ethanolic sodium hydroxideare added and refluxing is continued for 6 hours. The mixture isconcentrated to a small volume, acidified with hydrochloric acid,extracted with diethyl ether and the extract evaporated. The residue isdistilled (bulb to bulb) and the fraction boiling at 145°/0.1 mmHgcollected, to yield the benzofuran-2-yl-acetic acid.

The solution of 10.5 g thereof in 50 ml of tetrahydrofuran is added tothe stirred and refluxing mixture of 3.4 g of lithium aluminum hydridein 50 ml of tetrahydrofuran. After 12 hours of refluxing, the mixture iscooled in ice and decomposed with 3.4 ml of water, 3.4 ml of 15% aqueoussodium hydroxide and 10.2 ml of water. The inorganic salts are filteredoff washed with diethyl ether, the filtrate dried and evaporated toyield the 2-(2-hydroxyethyl)-benzofuran.

To the solution of 3.25 g thereof in 10 ml of pyridine 5.7 g ofp-toluenesulfonyl chloride are added while stirring at 5°. After 2 hoursthe mixture is poured onto ice, the solid collected and recrystallizedfrom ethyl acetate-petroleum ether, to yield the2-(2-tosyloxyethyl)-benzofuran.

The mixture of 4.55 g thereof, 2.64 g of 4-hydroxy-4-phenylpiperidineand 10 g of sodium carbonate in 100 ml of 4-methyl-2-pentanone isstirred and refluxed for 2 days. It is filtered, the filtrateevaporated, the residue dissolved in hot isopropanol, treated withcharcoal, filtered and on cooling the2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-benzofuran crystallizes out,it melts at 195°-197°.

EXAMPLE 21

To lithium diisopropylamide in 50 ml of tetrahydrofuran, prepared from2.25 ml of diisopropylamine and 10 ml of 1.6 N n-butyl lithium in hexaneat -70° under nitrogen, is added 2.0 g of thianapthene in 20 ml oftetrahydrofuran while stirring. After 1 hour, the solution of 2.65 g of2-[2-(4-oxopiperidino)-ethyl]-1,4-benzodioxan in 20 ml oftetrahydrofuran is added and, after standing overnight, the mixture isdecomposed with 9 ml of saturated aqueous ammonium chloride. The organicphase is separated, dried, evaporated, the crystalline residue washedwith water and recrystallized from ethanol-acetone, to yield the2-[2-(4-hydroxy-4-(2-benzothienyl)-piperidino)-ethyl]-1,4-benzodioxanmelting at 175°-178°.

EXAMPLE 22

The solution of 6 g of1-[2-(1,4-benzodioxan-2-yl)-acetyl]-4-allyloxy-4-phenylpiperidine in 50ml of tetrahydrofuran is added to the stirred suspension of 2 g oflithium aluminumhydride in 100 ml of tetrahydrofuran. After stirring themixture at room temperature overnight, it is cooled in an ice bath and 2ml of water, 4 ml of 15% aqueous sodium hydroxide and 6 ml of water areadded. After filtration and removal of the solvent, the residue isdissolved in the minimum amount of ethanol, and the solution isacidified with ethereal hydrogen chloride to yield the2-[2-(4-allyloxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxanhydrochloride, m.p. 195°.

The starting material is prepared as follows: The mixture of 25 g of4-hydroxy-4-phenylpiperidine and 50 ml of ethyl trifluoroacetate isrefluxed overnight and evaporated. The residue is taken up in benzene,the solution washed with 1N hydrochloric acid, dried and evaporated. Theresidue is recrystallized from ethyl acetate-petroleum ether, to yieldthe 1-trifluoroacetyl-4-hydroxy-4-phenylpiperidine melting at 123°-125°.

The solution of 15 g thereof in 50 ml of dimethylformamide is addeddropwise to the suspension of 3.6 g of a 50% sodium hydride mineral oildispersion, prewashed with pentane, in 50 ml of dry dimethylformamidewhile stirring and cooling with an ice bath. After one hour, 8.6 ml ofallyl bromide are added, while continuing the cooling in ice andstirring. After standing at room temperature overnight, the excesssodium hydride is destroyed by the addition of a few drops of aceticacid and the mixture is evaporated. The residue is dissolved in ethylacetate, the solution washed with water and saturated aqueous sodiumchloride, dried and evaporated. To the residue is added 140 ml ofmethanol and the solution of 14 g of potassium carbonate in 59 ml ofwater. After stirring for 3 hours at room temperature, the mixture isevaporated, the residue taken up in ethyl acetate, the solutionextracted with 1N hydrochloric acid and the extract basified withaqueous sodium hydroxide. The mixture is re-extracted with methylenechloride, the extract washed with water, dryed and concentrated to yield4-allyloxy-4-phenylpiperidine, which is used as such without furtherpurification.

The solution of 3.26 g thereof in 30 ml of tetrahydrofuran is addeddropwise to the stirring solution of 2.9 g of1,4-benzodioxan-2-yl-acetic acid and 2.9 g of 1,1'-carbonyldiimidazolein 30 ml of tetrahydrofuran. The mixture is allowed to stir overnightand the solvent is evaporated. The residue is taken up in ethyl acetate,the solution washed with water, 1N hydrochloric acid and water again,and evaporated to yield the1-[2-(1,4-benzodioxan-2-yl)-acetyl]-4-allyloxy-4-phenylpiperidine, whichis not further purified.

In like manner, using molar equivalents and the requisite startingmaterials, the 4-propargyloxy-4-phenylpiperidine, b.p. 140°-145°/0.07 mmHg and the 4-methoxy-4-(p-chlorophenyl)piperdine are obtained, thehydrochloride of the latter melts at 238°-242°.

EXAMPLE 23

The mixture of 6.2 g of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 4.0 g of4-propargyloxy-4-phenylpiperidine, about 10 g of anhydrous sodiumcarbonate and 100 ml of 4-methyl-2-pentanone is stirred and refluxed for48 hours. After filtration and removal of the solvent, the residue isredissolved in the minimum amount of ethanol and this solution acidifiedwith ethanolic hydrogen chloride, to yield the2-[2-(4-propargyloxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxanhydrochloride melting at 195°-196°.

EXAMPLE 24

To the solution of 3.2 g of 2-bromopyridine in 50 ml of tetrahydrofuranis added 12.5 ml of 1.6 N n-butyl lithium in hexane, while stirring at-75°. After one hour the solution of 2.65 g of2-[2-(4-oxopiperidino)-ethyl]-1,4-benzodioxan in 10 ml oftetrahydrofuran is added while stirring. After standing overnight atroom temperature, the mixture is decomposed with 10 ml of saturatedaqueous ammonium chloride. The organic solvent layer is separated,dried, evaporated and the residue strongly basified with aqueousammonium hydroxide. The mixture is extracted with ethyl acetate, theextract washed with water, dried and evaporated. The residue issuspended in 10 ml of ethanol, the suspension neutralized with ethanolichydrogen chloride and the precipitate recrystallized fromethanol-diethyl ether, to yield the2-[2-(4-hydroxy-4-(2-pyridyl)-piperidino)-ethyl]-1,4-benzodioxandihydrochloride, melting at 260°-262° with decomposition.

The analogously prepared 3-pyridyl-isomer melts at 245°-250° (dec.);both compounds are identical with those illustrated by Example 8, Nos.13 and 14.

I claim:
 1. A compound corresponding to the formula ##STR8## wherein Phis unsubstituted 1,2-phenylene or 1,2-phenylene substituted by one ortwo members selected from lower alkyl, hydroxy, mercapto, lower alkoxy,lower alkylenedioxy, benzyloxy, lower alkylthio, halogeno,trifluoromethyl, nitro, or amino; n is an integer from 1 to 4; each of pand q is an integer from 1 to 3, but (p + q) = 4; each of R₁ and R₂ ishydrogen or lower alkyl; R₃ is hydrogen, hydroxy, lower alkoxy, lower 2-or 3-alkenyloxy, lower 2- or 3-alkynyloxy, lower or higher alkanoyloxyand R₄ is unsubstituted furyl, thienyl, benzofuryl or benzothienyl, orsaid heterocyclics mono- or disubstituted by lower alkyl, ortherapeutically acceptable acid addition salts thereof.
 2. A compound asclaimed in claim 1, in which formula the moiety Ph is 1,2-phenyleneunsubstituted, mono- or disubstituted by alkyl, alkoxy or alkylthio withup to 4 carbon atoms each, halogeno or trifluoromethyl; n is an integerfrom 2 to 4, each of p and q is the integer 2, each of R₁ and R₂ ishydrogen or alkyl with up to 4 carbon atoms, R₃ is hydrogen, hydroxy,alkoxy, 2- or 3-(alkenyloxy or alkynyloxy) with up to 4 carbon atoms oralkanoyloxy with up to 16 carbon atoms and R₄ is 2- or 3-furyl or-thienyl; or therapeutically acceptable acid addition salts thereof. 3.A compound as claimed in claim 2 and corresponding to the formula##STR9## wherein R is hydrogen, alkyl, alkoxy or alkylthio with up to 4carbon atoms each, halogeno or trifluoromethyl, x is the integer 1 or 2,y is an integer from 2 to 4, R" is hydrogen, hydroxy, alkoxy, 2- or3-(alkenyloxy or alkynyloxy) with up to 4 carbon atoms or alkanoyloxywith up to 16 carbon atoms and R' is 2- or 3-furyl or -thienyl; ortherapeutically acceptable acid addition salts thereof.
 4. A compound asclaimed in claim 3 in which formula R is hydrogen, methyl, ethyl,methoxy, ethoxy, methylthio, ethylthio, fluoro, chloro ortrifluoromethyl, x is the integer 1 or 2, y is the integer 2 or 3, R" ishydrogen, hydroxy, methoxy, ethoxy, allyloxy, propargyloxy, oralkanoyloxy with 2 to 12 carbon atoms and R' is 2- or 3-furyl or-thienyl; or therapeutically acceptable acid addition salts thereof. 5.A compound as claimed in claim 1 and being the levorotatory opticalantipode thereof.
 6. A compound as claimed in claim 3 and being the2-[2-(4-hydroxy-4-thienyl-2-piperidino)-ethyl]-1,4-benzodioxan, or atherapeutically acceptable acid addition salt thereof.
 7. A neurolepticpharmaceutical composition comprising a neuroleptically effective amountof a compound as claimed in claim 1, together with a pharmaceuticalexcipient.
 8. A method of treating agression, agitation, anxiety or painin mammals, which consists in administering to said mammal enterally orparenterally a neuroleptically effective amount of a composition claimedin claim 7.